Long-term results of liver transplantation for over 60 years old patients with hepatitis B virus-related end-stage liver disease

Guangzhou,China

Introduction

At present,the relative shortage of donors and the increasing need for a cadaveric liver have led to debate over the optimal use of donated,cadaveric organs in China.At the same time,the improvement of surgical techniques,anesthesia,intensive care and immunosuppressive treatment has widened indications of liver transplantation,even for elderly patients.Liver transplantation for patients aged over 60 years has been reported in Western countries,but the results were controversial.Some reports[1-5]concluded that advanced age was no longer a contraindication to liver transplantation and that satisfactory patient survival and graft survival could be achieved; others[6-9]found a significantly lower survival rate in patients older than 60 years.The commonly recognized indications for liver transplantation are hepatitis C virus,primary biliary cirrhosis or alcoholic liver disease,which are different from those in China.Primary liver disease is recognized to in fluence the outcome of liver transplantation.In patients with hepatitis C virus-related end-stage liver disease (ESLD),8%-44% may have virus recurrence and develop cirrhosis within 5-10 years after transplantation.[10]

In China,chronic hepatitis B virus (HBV) infection is the most common etiology of ESLD; HBV-related ESLD is the leading indication for liver transplantation.[11,12]As life expectancy is increased,the demand for liver transplantation among elderly patients with HBV-related ESLD is also increasing in China.However,the long-term results of elderly patients after liver transplantation have not been comprehensively studied.We still do not know the in fluence of HBV infection on the prognosis of liver transplantation in elderly patients and their survival rate compared with that of younger patients.The present study aimed to present our singlecenter experience with liver transplantation for elderly recipients with HBV-related ESLD and compared their clinical outcomes with those of younger recipients.

Methods

Patients

A total of 365 patients with HBV-related ESLD received primary liver transplantations at our center between December 2003 and December 2005.The patients were divided into two groups according to age:older group,patients aged ≥60 years (n=60); and younger group,patients aged between 18-59 years (n=305).

Study variables

The following variables were analyzed:age,gender,preoperative characteristics of the recipients [including chronic diseases such as diabetes mellitus,cardiovascular,respiratory,renal and neurological disorders,Child-Pugh classification,the mean unmodified model for endstage liver disease (MELD) scores],intraoperative blood loss,cold ischemic time,time of mechanical ventilation in intensive care unit,postoperative complications[including infection,rejection,vascular and biliary complication,graft-versus-host disease (GVHD),HBV and hepatocellular carcinoma (HCC) recurrence].Actuarial survival rates of patients at 1,3,5 and 8 years after liver transplantation were recorded.Risk factors for death in the older group were also analyzed,while comparing deceased vs surviving patients aged over 60 years by univariate and multivariate analyses.

HBV recurrence

Prophylaxis of HBV recurrence combined with nucleotide analogs and hepatitis B immune globulin(HBIG) has been introduced in our center since October 2003.Lower doses of HBIG were given intramuscularly to maintain the level of anti-HBs ＞300 IU/L within six months and ＞100 IU/L six months later after liver transplantation.The optimal timing of preoperative antiviral therapy depends on the expected waiting time for liver transplantation and the patient's condition.Therapeutic regimen included:(i) using lamivudine as first-line therapy,adding or substituting adefovir dipoxil for lamivudine after appearance of lamivudine resistance; (ii) using entecavir when transplant is imminent (within one month).HBV recurrence was diagnosed after liver transplant when circulating HBsAg was detected in the serum,even in the absence of hepatic in flammation or abnormal liver enzymes,serum HBsAg and HBV DNA tests that were always positive postoperatively were excluded.[11]

Recurrence of HCC

Liver function and tumor markers were monitored in patients with HCC.Moreover,Doppler ultrasound examination was carried out monthly and thoracoabdominal enhanced computed tomography or contrastenhanced ultrasonography in every three months.Patients with suspicious recurrence or metastasis were subjected to positron emission tomography/computed tomography to locate the lesion.Once HCC recurrence or metastasis was confirmed,patients were recommended to receive treatments such as radiofrequency ablation,transarterial chemoembolization,alcohol injection,or resection.

Statistical analysis

Statistical analyses were performed with statistical software (SPSS 13.0,Chicago,IL,USA).Categorical variables were summarized as frequencies and percentages and analyzed using the Chi-square test or Fisher's exact test to compare the distributions between the older and younger groups.Continuous variables were expressed as mean±SD and compared using the paired t test.Patient survival was estimated using the Kaplan-Meier method from the date of surgery to that of death or October 2013.A multivariate stepwise logistic regression model was used to detect risk factors of death in the group of elderly patients,comparing recipient and surgery variables between deceased and surviving patients aged over 60 years.P values were two-sided and considered statistically significant at ≤0.05.

Results

Preoperative features

The mean age was 65.1±3.5 years (range 60-75) in the older group,whereas it was 46.1±8.8 years (range 18-59)in the younger group.In the older group,51 patients were men and 9 women,whereas in the younger group,276 patients were men and 29 women (Table 1).

Table 1.Preoperative characteristics of older and younger recipients of liver transplantation

Except for age and preexisting chronic disease,no statistically significant differences were observed in the preoperative characteristics between the older and younger groups,including male to female ratio,Child-Pugh class,MELD score and previous abdominal surgery.

Operation and immunosuppression

All transplants were performed using the piggy-back technique without veno-venous bypass.Simultaneous in situ flushing via the portal vein and the aorta was performed,and cold Celsior or University of Wisconsin solution was used for flushing and storage.The initial immunosuppression regimen after liver transplantation was composed of tacrolimus (Prograf,FK506) or cyclosporine with corticosteroids.The doses of these agents were adjusted according to the whole blood concentration.The target whole blood level of tacrolimus varied from 8 to 12 ng/mL during the first three months,and that of cyclosporine varied from 150 to 200 ng/mL during the same period.The doses were also adjusted according to the results of renal function tests and other side-effects of the agents.The initial dose of steroids was reduced rapidly and withdrawn at 3 to 6 months after transplantation.Immunosuppressant regimens were similar between the two groups.

Operation and postoperative complications

No statistical significance was observed in operative characteristics such as intraoperative blood loss and cold ischemic time between the older and younger groups.Inthe older group,there were 13 (21.7%) episodes of severe infections after liver transplantation,which are more than those [57 (18.7%)] in the younger group (P=0.593).Similarly,no difference was noted in the number of episodes of other postoperative complications between the two groups (Table 2).

Table 2.Operation and postoperative characteristics of older and younger recipients of liver transplantation

Table 3.Characteristics of hepatitis B infection and HCC before and after liver transplantation (n,%)

Characteristics of HBV infections and HCC recurrence

Fig.Survival function estimate between the older and younger groups.

Table 4.Causes of death of the older and younger recipients of liver transplantation (n,%)

No significant difference was observed in indications for liver transplantation between the two groups(Table 3),nor in the characteristics of HBV infection.The 1-,3-,5- and 8-year HBV recurrence and the 3-,5- and 8-year HCC recurrence rates were higher in the younger group than in the older group although the differences were not statistically significant.No patients in the older group were found to have HBV recurrence at follow-up.HCC recurrence was mainly seen in the first year in the older group,but increased with years within the first 5 years after liver transplantation in the younger group (from 12.3% to 36.9%).

Actuarial patient survival and causes of death

There was no significant difference in overall survival between the two groups (P=0.565) (Fig.).The 1-,3-,5- and 8-year actuarial survival rates were 81.6%,71.6%,66.7% and 63.3% respectively for the older group and 84.9%,77.7%,70.8% and 65.6% respectively for the younger group.

In 127 deaths,22 were in the older group and 105 in the younger group.The causes of death are listed in Table 4.HCC recurrence and biliary complications were the two main causes of death in both groups,but there was no significant difference in the causes of death between the groups.

Risk factors of death in the older group

Univariate analyses showed that the risk factorsof death in the older group were Child-Pugh class C(P=0.032),pre-liver transplant renal insufficiency (P=0.005),MELD score ＞30 (P=0.025),and diabetes mellitus (P=0.038) (Table 5).But multivariate analysis (Table 6)revealed that the only death-related factor in elderly patients undergoing liver transplantation was pre-liver transplant renal insufficiency (P=0.014; odds ratio=3.615;95% confidence interval 1.482-8.352).

Table 5.Univariate analysis of risk factors of death in the elderly patient group

Table 6.Multivariate analysis of risk factors of death in the elderly patient group

Discussion

HBV infection is a global health problem.Two billion people have been infected with HBV worldwide,and 360 million people are suffering from chronic HBV infection,50% of them are from China.[12]The prevalence of HBV-related liver disease increases with age,so the number of elder patients is increasing in the waiting list of liver transplantation.However,the data on the survival of this population in China are scant.

Advancing age is an independent risk factor for the development of some chronic diseases such as diabetes mellitus,hypertension,coronary artery disease (CAD)and malignancy.Blei et al[13]reported a prevalence of 24.5% for moderate to severe CAD in elder patients with liver disease.Moreover,the mortality and morbidity of patients with CAD who undergo liver transplantation could be as high as 26% and 38% respectively.[14]As for the severity of liver disease itself,Jiménez et al[4]found that at the time of transplantation,older recipients were in a better clinical condition according to the Child-Pugh score,but the United Network for Organ Sharing status did not show it.According to our pre-transplant evaluation of older transplant candidates,preexisting chronic diseases were more common in the older group than in the younger group (38.3% vs 7.2%).The most common chronic diseases before transplantation in the older group were hypertension (n=14),diabetes mellitus(n=12),CAD (n=8) and renal insufficiency (n=8),but the severity of these diseases was mild to moderate and additional treatment was unnecessary during the preoperative period.In China,older patients and their family members are usually reluctant to receive transplantation if no other severe medical comorbidities are found before the operation.Between the two groups,no difference was found in Child-Pugh class and MELD scores before transplantation,i.e.50.0% of older patients and 46.6% of younger patients were classified as Child-Pugh class C (P＞0.05).

Intraoperative blood loss was more in the younger group than in the older group,but the difference was not significant.This finding was not consistent with other report.[2]Jiménez et al[4]reported that veno-venous bypass was frequently used in younger patients and was associated with hemodynamic instability,coagulopathy and intraoperative bleeding.In our center,the piggy-back technique was frequently used in older or younger patients,but veno-venous bypass was seldom performed.[15]Regarding postoperative complication,the overall rates of severe infections,acute rejection,and biliary and vascular complication were not different between the two groups.GVHD following liver transplantation is a rare but fatal complication.The difference of age between donor and recipient is a risk factor,particularly when the donor is substantially younger than the recipient.[16]According to our data,however,the incidence of GVHD in the older group was similar to that in the younger group and only one patient aged 70 years suffered from GVHD.

In our study,HBV-related ESLD was divided into four types:fulminant hepatic failure,chronic hepatitis,cirrhosis and HCC.The proportions of these four diseases were similar in the older and younger groups.Although the rate of HBeAg and HBV-DNA positive in the younger group was higher than that in the older group,the difference was not statistically significant.Thus this finding is different from the statement of the European Association for the Study of the Liver.The patients with HBeAg-negative chronic hepatitis tended to be older,male and to present with severe necro-in flammation and cirrhosis.[17]Treatment of HBV recurrence in the liver graft is also a major clinical challenge,but the combination of nucleotide analogs before and after liver transplantation with HBIG after liver transplantation has become the standard of care for most liver transplant programs in China.Multiple liver studies[18-20]showed that the mean reinfection rate was only 5.2% (range 0-18%) after one to two years.In our study,this combination of therapies also gave the same promising results at eight years,with only 24 (7.9%)cases of HBV recurrence in the younger group and none in the older group.The impact of HBV genotype on reinfection has only recently been assessed.[21,22]In London,genotypes A,D and A/D accounted for 89% of the European population undergoing liver transplantation.HBV recurrence occurred in 40%,a median of 10 months after liver transplantation,and 22% died.[21]In China,genotypes B and C were the main genotypes.Whether this contributes to the lower HBV recurrence needs further investigation.The advent of adefovir dipoxil and entecavir also provided a safe and efficacious therapeutic option for patients with lamivudine-resistant infection,[23,24]only two patients with HBV recurrence died.

As discussed above,the results of liver transplantation in older patients in different liver transplantation centers were con flicting.Two principal reasons may account for this discrepancy.First,long-term data about liver transplantation in older patients are now available.Collins et al[6]revealed that older recipients at their center did as well as younger recipients in early years after liver transplantation; but their long-term survival results were not encouraging.The 5- and 10-year patient survival rates were 52% and 35% in older patients and 75% and 60% in younger patients (P＜0.05).Data from the European Liver Transplantation Registry draw the same conclusion.[25]Second,preoperative condition may play an important role in the outcome in older patients.Levy et al[26]found no in fluence on mortality in patients at home with increasing age.Elderly patients who were at hospitals including the intensive care unit prior to the transplant had significantly worse outcomes than hospitalized younger patients.Garcia et al[7]and Jiménez et al[4]thought that preoperative higher Child-Pugh scores had a significantly negative impact on the mortality of patients aged over 60 years.These studies all advocated the allocation of liver transplants to low-risk seniors.In addition,Cross et al[27]found that patients aged from 60 to 64 years undergoing transplantation showed a best survival rate although it was not statistically significant.They attributed this result to the rigorous preoperative examination by excluding serious comorbidities,which may in turn improve outcomes.

In our study,no significant differences were seen in 1-,3-,5- and 8-year actuarial survival rates in patients older than 60 years at the time of transplantation compared with those younger than 60 years.We also found that the main causes of death were recurrence of HCC and biliary complications in both the older and younger groups.These results are inconsistent with those published by Collins et al,[6]who found that de novo neoplasia was the overwhelming etiology of late mortality in elderly recipients,whereas deaths caused by infections occurred more frequently in young adults,although the difference was not statistically significant.In our study,risk factors indicated that patients aged over 60 years with Child-Pugh class C,MELD scores＞30,diabetes mellitus or renal insufficiency had a higher risk of death.Whereas multivariate analyses showed that only pre-liver transplant renal insufficiency remained as the universal risk factor for poor posttransplant prognosis.As the only factor,renal insufficiency deteriorates liver function reserve (Child-Pugh class C),the micro-angiopathic manifestations of diabetic patients,and the natural deterioration of organs with age.

In conclusion,liver transplantation is safe and feasible in patients with HBV-related ESLD aged over 60 years compared with younger patients.Combined therapies of HBIg and nucleoside can effectively prevent HBV recurrence and contributes to the improvement of long-term survival of patients with HBV-related ESLD after liver transplantation.Older patients with renal insufficiency should be transplanted at an earlier stage.

Contributors:YSH proposed the study.YSH and YHM performed research,wrote the first draft and contributed equally to this article.All authors contributed to the design and interpretation of the study and to further drafts.CGH is the guarantor.

Funding:This study was supported by grants from the Major State Basic Research Development Program of China (973 Program)(2009CB522404),Science Technology Research Development Program of Guangdong Province (2011B031800060) and Science Technology Research Development Program of Guangzhou(2011Y1000332).

Ethical approval:Not needed.

Competing interest:No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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